Brain-specific repression of AMPKα1 alleviates pathophysiology in Alzheimer’s model mice
Helena R. Zimmermann, … , C. Dirk Keene, Tao Ma
Helena R. Zimmermann, … , C. Dirk Keene, Tao Ma
Published March 26, 2020
Citation Information: J Clin Invest. 2020;130(7):3511-3527. https://doi.org/10.1172/JCI133982.
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Research Article Aging Neuroscience

Brain-specific repression of AMPKα1 alleviates pathophysiology in Alzheimer’s model mice

Abstract

AMPK is a key regulator at the molecular level for maintaining energy metabolism homeostasis. Mammalian AMPK is a heterotrimeric complex, and its catalytic α subunit exists in 2 isoforms: AMPKα1 and AMPKα2. Recent studies suggest a role of AMPKα overactivation in Alzheimer’s disease–associated (AD-associated) synaptic failure. However, whether AD-associated dementia can be improved by targeting AMPK remains unclear, and roles of AMPKα isoforms in AD pathophysiology are not understood. Here, we showed distinct disruption of hippocampal AMPKα isoform expression patterns in postmortem human AD patients and AD model mice. We further investigated the effects of brain- and isoform-specific AMPKα repression on AD pathophysiology. We found that repression of AMPKα1 alleviated cognitive deficits and synaptic failure displayed in 2 separate lines of AD model mice. In contrast, AMPKα2 suppression did not alter AD pathophysiology. Using unbiased mass spectrometry–based proteomics analysis, we identified distinct patterns of protein expression associated with specific AMPKα isoform suppression in AD model mice. Further, AD-associated hyperphosphorylation of eukaryotic elongation factor 2 (eEF2) was blunted with selective AMPKα1 inhibition. Our findings reveal isoform-specific roles of AMPKα in AD pathophysiology, thus providing insights into potential therapeutic strategies for AD and related dementia syndromes.

Authors

Helena R. Zimmermann, Wenzhong Yang, Nicole P. Kasica, Xueyan Zhou, Xin Wang, Brenna C. Beckelman, Jingyun Lee, Cristina M. Furdui, C. Dirk Keene, Tao Ma

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Figure 6

Reduction of brain AMPKα1 mitigates impairments of cognition and synaptic plasticity associated with APP/PS1 AD model mice.

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Reduction of brain AMPKα1 mitigates impairments of cognition and synapti...
(A) Genetic reduction of AMPKα1, but not AMPKα2, corrected eEF2 hyperphosphorylation in hippocampi of APP/PS1 mice. n = 4. WT versus α2/APP, *P = 0.0464; WT versus APP, **P = 0.0029; α1/ΑPP versus α2/APP, #P = 0.006; α1/ΑPP versus APP, ***P = 0.0003; 1-way ANOVA with Tukey’s post hoc test. F = 8.455. (B) Unaltered periphery time in OF task. n = 28, 20, 13, and 20. (C) Preference for familiar (white) or novel (purple) objects in the NOR task. n = 12, 12, 10, and 10. WT, *P < 0.0001; APP, P = 0.7602; α1/APP, **P < 0.0001; α2/Tg, ***P = 0.0123, unpaired t test. (D) Escape latency or latencies in the hidden-platform MWM. Escape latency of day 5 was significantly higher in APP and α2/APP mice. n = 18, 18, 9, and 15. α1/ΑPP versus α2/APP, *P = 0.0259; WT versus α2/APP, **P = 0.0013; APP versus α1/APP, **P = 0.0064; WT versus APP, ***P < 0.0001. F = 10.53. (E) Target quadrant occupancy during probe trial of MWM task. WT versus APP, *P = 0.0298; WT versus α2/APP, **P = 0.003, 1-way ANOVA with Tukey’s post hoc test. F = 5.259. (F) Hippocampal LTP. HFS denoted by arrow. n = 18, 12, 12, 7, 8, and 9. (G) Representative fEPSP traces before and after HFS. (H) Quantification of the fEPSP slope 90 minutes after HFS. WT versus APP, ***P = 0.0009; WT versus α2/APP, **P = 0.0011; α1/cre versus APP, *P = 0.0017; α1/cre versus α2/APP, #P = 0.0017, 1-way ANOVA with Tukey’s post hoc test. F = 7.519. (I and J) Representative images and quantification of cortical Aβ plaque deposition. n = 9 slices/3 mice. (K and L) Representative images and quantification of hippocampal Aβ plaque deposition. n = 9 slices/3 mice. Scale bars: 100 μm (×20 images); 50 μm (×60 images). Box-and-whisker plots represent the interquartile range, with the line across the box indicating the median. Whiskers show the highest and lowest values detected.